Synthetic intermediate for epothilone derivative and production method thereof

Abstract

The beta-keto ester compound, beta-hydroxy acid compound and acetonide form of a 1,3-diol derivative of the formulas (I), (V) and (VIII)wherein each symbol is as defined in the specification, are useful as a synthetic intermediate for an epothilone derivative being developed as a pharmaceutical agent having an antitumor activity.

What is claimed is:  
     
       1. A β-keto ester compound represented by the following formula                    
        wherein R 4  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, or an optically active form thereof.  
     
     
       2. The compound of  claim 1 , wherein R 4  is hydrogen atom, or an optically active form thereof. 
     
     
       3. The compound of  claim 1 , wherein R 4  is alkyl group having 1 to 6 carbon atoms, or an optically active form thereof. 
     
     
       4. A production method of a β-keto ester compound  claim 1 , which comprises condensation of a 2-cyano-2,2- dimethylacetate represented by the following formula                    
        wherein R 1  is alkyl group having 1 to 6 carbon atoms, with an alkyl ester represented by the following formula                    
        wherein R 4  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, is the presence of a strong base.  
     
     
       5. The production method of  claim 4 , wherein R 4  is hydrogen atom. 
     
     
       6. The production method of  claim 4 , wherein R 4  is alkyl group having 1 to 6 carbon atoms. 
     
     
       7. The production method of  claim 4 , comprising adding lithium diisopropylamide as a strong base to a mixture of 2-cyano- 2,2-  dimethylacetate represented by the formula (II) and an alkyl ester represented by the formula (III). 
     
     
       8. The production of  claim 4 , which comprises adding cyanoacetate of the following formula                    
        wherein R 1  is alkyl group having 1 to 6 carbon atoms, and dimethyl sulfate continuously or discontinuously to a sodium hydride-containing tetrahydrofuran solution to give 2-cyano-2, 2-dimethylacelate of the formula (II), and condensation thereof with an alkyl ester of the formula (III).  
     
     
       9. A β-hydroxy acid compound represented by the following formula                    
        wherein R 2  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, and R 4  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, provided that when R 4 , is alkyl group having 1 to 6 carbon atoms, R 2  should be tert-butyl-group, an optically active form thereof or a salt thereof.  
     
     
       10. The compound of  claim 9 , wherein R 4 , is hydrogen atom, an optically active form thereof or a salt thereof. 
     
     
       11. The compound of  claim 9 , wherein R 4  is alkyl group having 1 to 6 carbon atoms and R 2  is tert-butyl group, an optically active form thereof or a salt thereof. 
     
     
       12. A production method of a β-hydroxy acid compound represented by the formula (V) of  claim 9 , which comprises reducing a β-keto ester compound represented by the following formula                    
        wherein R 2  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, and R 4  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, provided that when R 2  is alkyl group having 1 to 6 carbon atoms, R 2  should be tert-butyl group, or a salt thereof.  
     
     
       13. The production method of  claim 12 , wherein  R4 , is alkyl group having 1 to 6 carbon atoms and R 2  is tert-butyl group. 
     
     
       14. The production method of  claim 13 , wherein the reduction is carried out using alkali borohydride and divalent metal chloride. 
     
     
       15. The production method of  claim 12 , wherein R 2 , is hydrogen atom. 
     
     
       16. The production method of  claim 15 , wherein R 2  is alkyl group having 1 to 6 carbon atoms. 
     
     
       17. The production method of  claim 16  wherein the alkyl group having 1 to 6 carbon atoms is tert-butyl group. 
     
     
       18. The production method of  claim 15 , wherein the reduction carried out using sodium borohydride. 
     
     
       19. The production method of  claim 14 , wherein the β-keto ester compound of the formula (I′), wherein R 2  is alkyl group having 1 to 6 carbon atoms and R 4  is hydrogen atom, is reduced to give a β-hydroxy acid compound (V-4) represented by the following formula                    
        wherein R 2 , is alkyl group having 1 to 6 carbon atoms, which is a compound of the formula (V) wherein R 2  is alkyl group having 1 to 6 carbon atoms and R 4  is hydrogen atom, and the p-hydroxy acid compound (V-4) is subjected to alkali hydrolysis to give a β-hydroxy acid compound (V-5) of the following formula                    
        which is a compound of the formula (V) wherein R 2  and R 4  are hydrogen atoms.  
     
     
       20. The production method of  claim 19 , wherein the resulting β-hydroxy acid compound (V-5) is optically resolved to give a βhydroxy acid compound (V-6) of the following formula                    
        or a salt thereof, which is then esterified with an alkylating agent to give a β-hydroxy acid compound (V- 7 ) represented by the following formula                    
        wherein R 3  is alkyl group having 1 to 6 carbon atoms, which is an optically active compound of the formula (V) wherein R 2  is alkyl group having 1 to 6 carbon atoms and R 4  is hydrogen atom.  
     
     
       21. The production method of  claim 19 , wherein each alkyl group having 1 to 6 carbon atoms is tert-butyl group. 
     
     
       22. A production method of a β-hydroxy acid compound (V-6) represented by the following formula                    
        or a salt thereof, which is an optically active compound represented by the formula (V) of  claim 9 , wherein R 2  and R 4  are hydrogen atoms, which comprises optically resolution of the β-hydroxy acid compound (V-5) represented by the following formula                    
     
     
       23. The production method of  claim 22 , wherein the βhydroxy acid compound (V-5) is converted to a salt with an optically active amine compound and optically resolved. 
     
     
       24. A production method of a β-hydroxy acid compound (V-7) represented by the following formula                    
        wherein R 3  is alkyl group having 1 to 6 carbon atoms, which is an optically active compound represented by the formula (V) of  claim 9 , wherein R 2  is alkyl group having 1 to 6 carbon atoms and R 4  is hydrogen atom, which comprises esterification of a β-hydroxy acid compound (V-6) represented by the following formula                    
        or a salt thereof with an alkylating agent.  
     
     
       25. An acetonide form of a 1,3-dial derivative, which is represented by the following formula                    
        or an optically active form thereof.  
     
     
       26. A production method of an acetonide form of a 1,3-dial derivative represented by the formula (VIII) of  claim 25 , or an optically active form thereof, which comprises conversion of a 1,3-diol derivative represented by the following formula                    
        or an optically active form thereof, to an acetonide form thereof.  
     
     
       27. The production method of  claim 26 , wherein the β-hydroxy acid compound of the following formula                    
        wherein R 2  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, or an optically active form thereof is reduced to give a 1,3-diol derivative of the formula (VII) or an optically active form thereof, which is converted to an acetonide form.  
     
     
       28. A production method of a 1,3-diol derivative represented by the following formula                    
        or an optically active form thereof, which comprises reducing a β-hydroxy acid compound represented by the following formula                    
        wherein R 2  is hydrogen atom or alkyl group having 1 to 6 carbon atoms, or an optically active form thereof.